High-risk rhabdomyosarcoma: maintenance chemotherapy can improve survival rates

Vinorelbine and low-dose cyclophosphamide therapies significantly increase overall 5-year survival in high-risk children with RMS, from 73.3% without maintenance therapy to 86.5%

Is preservation chemotherapy applicable to other solid tumors?

Maintenance therapy with vinorelbine and low-dose cyclophosphamide significantly increases overall 5-year survival in high-risk children with rhabdomyosarcoma, from 73.3% without maintenance therapy to 86.5%

The conclusions of the RMS25000 study, which was executed by the European Pediatric Soft Tissue Sarcoma Study Group (EpSSG), were presented by Gianni Bisogno, University Hospital Padua, at the plenary session during the 2018 ASCO Annual Meeting in Chicago on June 3, 2018.

Rhabdomyosarcoma (RMS) is a very rare tumor; 350 children are diagnosed with this disease in the USA and 320 in Europe each year. Adults can also fall ill. The very aggressive tumor can be cured in 70 to 80% of patients with modern intensive therapy. If metastases are already present at diagnosis or if a tumor recurs after initial therapy, the chances of recovery decrease.

90% of patients at high risk - defined by unfavorable localization, e.g. at the head, neck or pelvis, unfavorable histology and lymph node involvement - achieve complete remission through standard therapy consisting of intensive chemotherapy, radiotherapy, and surgery. Of these, 60 to 70 % have a long-term survival, 30 to 40 % have a relapse - usually in the first year. The aim of the RMS2005 study was therefore to investigate the role of maintenance therapy with vinorelbine and low-dose cyclophosphamide in patients who had achieved complete remission with standard therapy.

A look into maintenance chemotherapy over 6 months

The EpSSG study included 371 patients with pathologically proven RMS without metastases aged 0 to 21 years who had been pretreated with standard therapy. Randomized 186 patients were treated with 6 28-day cycles of vinorelbine (25 mg/m² days 1, 8 and 15) and cyclophosphamide (25 mg/m² daily), 185 received no maintenance therapy. This low-dose therapy caused fewer myelotoxic and infectious side effects than standard therapy. No cardiac, hepatic or renal toxicities occurred. "The toxicity was very acceptable," Bisogno commented.

In the maintenance therapy group, 77.6% of patients lived without renewed signs of disease after 5 years, in the comparison group it was 69.8% (p = 0.0613). Overall, 86.5 % of patients survived after 5 years of maintenance therapy, 73.7 % without maintenance therapy (p = 0.0111).

New therapy standard for high-risk RMS patients

"This study establishes a new therapeutic standard for patients with high-risk rhabdomyosarcoma," concluded Bisogno. In his opinion, maintenance chemotherapy should be investigated for other solid tumors in pediatrics.

Discutant Douglas S. Hawkins, Seattle Children's Hospital, University of Washington, Seattle, congratulated the EpSSG on this study. The group conducted a randomized study in an exceptionally rare disease. And it is only the third positive, randomized study in pediatric rhabdomyosarcoma. The first two positive studies were published in 1974 and 2014. Hawkings pointed out that selected high-risk patients had been enrolled in the RMS2005 study. Patients who did not respond completely radiologically in week 27 were excluded. Patients with the highest risk of recurrence, i.e. patients with alveolar rhabdomyosarcoma and regional lymph node infestation and patients with distant metastases, were also excluded. The EpSSG has therefore recently adapted its recommendations for maintenance therapy for patients with the highest risk. Hawkin concluded: "Maintenance chemotherapy has moderate toxicity and should be considered as a standard for high-risk patients with rhabdomyosarcoma after complete remission.

Bisogno G. et al. Maintenance low-dose chemotherapy in patients with high-risk (HR) rhabdomyosarcoma (RMS): A report from the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG).  2018 ASCO Annual Meeting, Chicago, June 1-5, 2018, Abstract LBA2. https://meetinglibrary.asco.org/record/161695/abstract